Half of all dementias start with damaged 'gatekeeper cells'
Once the cells are compromised, the brain's protective fort becomes leaky and allows blood toxins to trespass into the brain, damaging critical connections between brain areas, researchers say.

USC research sheds new light on how a breakdown in the brain's vascular system predates the accumulation of toxic plaques and tangles in the brain that bring about Alzheimer's disease. The research suggests an earlier target for preventing dementia and Alzheimer's.

Nearly 50 percent of all dementias, including Alzheimer's, begins with the breakdown of the smallest blood vessels in the brain and their protective "gatekeeper cells," according to a Keck School of Medicine of USC study.

That catastrophe causes a communications failure called small vessel disease. Many people with that disease also have white matter disease, the wearing away of fatty myelin that allows neurons to transfer messages within the brain network. In an animal model, researchers found that brain deterioration associated with dementia may start as early 40 in humans.

For more than 25 years, scientists have known that white matter disease impedes a person's ability to learn or remember new things, slows thinking and causes people to fall more often due to balance issues. They identified a link between crippled small blood vessels in the brain and white matter disease but didn't know what started that process until now.

"Many scientists have focused their Alzheimer's disease research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier -- with leaky blood vessels in the brain," said Berislav Zlokovic, senior author of the study and holder of the Mary Hayley and Selim Zilkha Chair in Alzheimer's Disease Research at the Keck School of Medicine.

The study, published in Nature Medicine on Feb. 5, explains that pericytes play a critical role in white matter health and disease via fibrinogen, a protein that circulates in blood. Fibrinogen develops blood clots so wounds can heal. When gatekeeper cells are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures, including axons (nerve fibers) and oligodendrocytes (cells that produces myelin), to die.

Axel Montagne, first author of the study, said he and his colleagues are the first to show that fibrinogen is a key player in non-immune white matter degeneration. The protein enters the brain through a leaky blood-brain barrier.

"We demonstrated that controlling fibrinogen levels can, in a mouse model, reverse or slow white matter disease, the harbinger to dementia," said Montagne, an assistant professor of research in physiology and neuroscience at the Zilkha Neurogenetic Institute at the Keck School of Medicine.

Dementia affects 50 million people worldwide and costs the world an estimated $818 billion, according to the World Health Organization.

As a research institution devoted to promoting health across the life span, USC has more than 70 researchers dedicated to the prevention, treatment and potential cure of Alzheimer's disease and other dementias.

A new villain to target

The study found about 50 percent fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas in postmortem Alzheimer's brains of humans compared to healthy brains.

To understand what was happening, USC-led researchers studied mice lacking in pericytes and compared them with a control group.

Using a MRI technique the Zlokovic Lab developed, they noticed 50 percent increased vessel leakage in mice that were 36 to 48 weeks old, roughly the equivalent of 70-year-old humans. The animal model replicated what scientists observed in the postmortem brains of people.

So they took a closer look.

The scientists also found reduced cerebral blood flow and increased accumulation of fibrinogen in the brains of mice deficient in gatekeeper cells. At 12 to 16 weeks old, the experimental mice had 10 times more fibrinogen in the corpus callosum compared to the control group. That region is the brain's central transit terminal that routes motor, sensory and cognitive information to their final destinations.

"Our observations suggest that once pericytes are damaged, blood flow in the brain reduces like a drain that is slowly getting clogged," said Angeliki Maria Nikolakopoulou, co-first author of the study and assistant professor of research in physiology and neuroscience at the Zilkha Neurogenetic Institute.

On the wheel

Researchers had the mice run on a wheel to test their subcortical brain region, the same area studied in postmortem humans. At first, the wheel had equally spaced rungs. After two weeks, scientists removed some of the rungs. When the experimental group was 12 to 16 weeks old, they reached a maximum speed that was about 50 percent slower than the control group.

"The mice deficient in pericytes function slower because there are structural changes in their white matter and a loss of connectivity among neurons," Zlokovic said.

The researchers used diffusion MRI techniques the Zlokovic Lab developed to see what was happening in the brain. They saw white matter changes in mice as early as 12 to 16 weeks old. Theoretically, that means white matter disease in humans could begin when they are just 40 years old, Montagne said.

"Pericytes are compromised early on," Montagne said. "Think of it as hair clogging a drain over time. Once the drain is clogged, cracks begin forming in the 'pipes' or brain's blood vessels. White matter frays and brain connections are disrupted. That's the beginnings of dementia."

Testing the poison

To confirm that fibrinogen proteins are toxic to the brain, researchers used an enzyme known to reduce fibrinogen in the blood and brain of mice. White matter volume in mice returned to 90 percent of their normal state, and white matter connections were back to 80 percent productivity, the study found.

"Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease," Zlokovic said. "It provides a target for treatment, but more research is needed. We must figure out the right approach.

"Perhaps focusing on strengthening the blood-brain barrier integrity may be an answer because you can't eliminate fibrinogen from blood in humans. This protein is necessary in the blood. It just happens to be toxic to the brain."

A pretty obvious connection with diabetes, high blood glucose etc. and the repeating theme of small blood vessel compromise that exists there.

Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease

Abstract
The ketogenic diet, originally developed for the treatment of epilepsy in non-responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B-Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed.

Too much cell biology for me, but it is open access for anyone who want to delve deeper.

This is a great thread. One of my main motivators for this WOE is brain health (and heart, liver, pancreas, kidneys, etc.); prevention of dementia and Alzheimer's disease. To me, weight loss is secondary and a bonus. I just started reading Amy Berger's The Alzheimer's Antidote (2017) and just put on hold Dale Bredesen's The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline (2017).

I, as well, am a fan of Dr. Ede. I look forward to her focusing on nutrition, as it has such an impact on overall health, and it's really the correct avenue to travel for medicine these days. She has so much to offer in this field.

The information about a ketogenic diet being protective of inflammation makes a lot of sense, and it also makes sense that reduced inflammation would encourage better health and elimination of the many symptoms of metabolic syndrome. When I get a blood test, I request an High Sensitivity C-reactive Protein (hsCRP) test which is used to measure my inflammation, and my last test result was 0.4 mg/L, indicating that my inflammation is under good control. The following metrics indicate hsCRP levels of inflammation:
- Low risk: less than 1.0 mg/L
- Average risk: 1.0 to 3.0 mg/L
- High risk: above 3.0 mg/L

I strongly believe following a strict LC/KD approach has a lot to do with being able to manage inflammation among other things.

If you look at what happens when our blood sugar is constantly goosed by fast-acting carbs, you see what was happening to me from other means; cortisol dumped into the bloodstream activates more insulin and more fat storage and... more cortisol.

Quote:

However, this effect is seen even within the normal population, without evidence of Cushing’s syndrome. In a random sample from North Glasgow, Scotland, cortisol excretion rates were strongly correlated to Body Mass Index (BMI) and waist measurements. Higher cortisol levels were seen in heavier people. Cortisol related weight gain particularly deposits fat in the abdomen, which results in an increased waist/hip ratio (WHR). This weight distribution of fat in the abdomen is more dangerous to the health than generalized fat.

Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease

Abstract
The ketogenic diet, originally developed for the treatment of epilepsy in non-responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B-Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed.

Too much cell biology for me, but it is open access for anyone who want to delve deeper.

I don't understand this either but wonder about the part talking about Oxygen. 2 years ago I had a colonoscopy. They told me my oxygen levels were at 100% and said they hardly ever see that, because most people are less than that.
So do you think that's a good or bad thing?

Yes. Ability to transport oxygen and extent of oxidative damage are two different things entirely.

There actually is some evidence for benefits from living in slightly hypoxic environments, though. Also for intermittent hypoxia intentionally applied. Sleep apnea is overkill, too much is damaging instead of triggering a beneficial response.

I remember wondering about this years ago when I noticed that a lot of higher longevity than usual claims were in people living at elevation. One problem with this is these places are sort of off the beaten track and might have escaped more exacting record keeping until fairly recently.

There was a story a while back showing traditional pearl divers having larger spleens. An increased reserve of oxygen-carrying red blood cells helps them stay under longer, I thought that was pretty cool.

There was a story a while back showing traditional pearl divers having larger spleens. An increased reserve of oxygen-carrying red blood cells helps them stay under longer, I thought that was pretty cool.

Now that's interesting because when I was a kid at the swimming pool I use to go underwater and see how long I could hold my breath. I went over a minute many times almost to 2 minutes probably but had to stop because the life guard told me not to. I would concentrate or meditate to stay under longer holding the ladder. I dreamed of snorkeling and scuba diving which I did when I was old enough to take myself
Maybe that effected my growing lungs?